Phosphoproteomics screen reveals akt isoform-specific signals linking RNA processing to lung cancer

Mol Cell. 2014 Feb 20;53(4):577-90. doi: 10.1016/j.molcel.2013.12.018. Epub 2014 Jan 23.

Abstract

The three Akt isoforms are functionally distinct. Here we show that their phosphoproteomes also differ, suggesting that their functional differences are due to differences in target specificity. One of the top cellular functions differentially regulated by Akt isoforms is RNA processing. IWS1, an RNA processing regulator, is phosphorylated by Akt3 and Akt1 at Ser720/Thr721. The latter is required for the recruitment of SETD2 to the RNA Pol II complex. SETD2 trimethylates histone H3 at K36 during transcription, creating a docking site for MRG15 and PTB. H3K36me3-bound MRG15 and PTB regulate FGFR-2 splicing, which controls tumor growth and invasiveness downstream of IWS1 phosphorylation. Twenty-one of the twenty-four non-small-cell-lung carcinomas we analyzed express IWS1. More importantly, the stoichiometry of IWS1 phosphorylation in these tumors correlates with the FGFR-2 splicing pattern and with Akt phosphorylation and Akt3 expression. These data identify an Akt isoform-dependent regulatory mechanism for RNA processing and demonstrate its role in lung cancer.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alternative Splicing*
  • Amino Acid Sequence
  • Animals
  • Gene Expression Regulation
  • Gene Expression Regulation, Neoplastic*
  • HeLa Cells
  • Histone-Lysine N-Methyltransferase / metabolism
  • Histones / metabolism
  • Humans
  • Lung Neoplasms / metabolism*
  • Mice
  • Mice, Nude
  • Molecular Sequence Data
  • Neoplasm Transplantation
  • Phosphoproteins / metabolism
  • Phosphorylation
  • Protein Isoforms / metabolism
  • Proteins / metabolism*
  • Proteomics
  • Proto-Oncogene Proteins c-akt / metabolism*
  • RNA / metabolism
  • Receptor, Fibroblast Growth Factor, Type 2 / metabolism
  • Sequence Homology, Amino Acid
  • Time Factors

Substances

  • Histones
  • IWS1 protein, mouse
  • Iws1 protein, human
  • Phosphoproteins
  • Protein Isoforms
  • Proteins
  • RNA
  • Histone-Lysine N-Methyltransferase
  • SETD2 protein, mouse
  • Set2 protein, human
  • FGFR2 protein, human
  • Fgfr2 protein, mouse
  • Receptor, Fibroblast Growth Factor, Type 2
  • AKT1 protein, human
  • AKT3 protein, human
  • Akt1 protein, mouse
  • Akt3 protein, mouse
  • Proto-Oncogene Proteins c-akt